Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

Abstract

The aim of the present study was to evaluate the toxicity and the activity of a new lipid complex formulation of amphotericin B (AMB) (LC-AMB; dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, and AMB) that can be produced by a simple process. Like other lipid formulations, this new complex reduced both the hemolytic activity of AMB (the concentration causing 50% hemolysis of human erythrocytes, >100 g/ml) and its toxicity toward murine peritoneal macrophages (50% inhibitory concentration, >100 g/ml at 24 h). The in vivo toxicity of the new formulation (50% lethal dose, >200 mg/kg of body weight for CD1 mice) was similar to those of other commercial lipid formulations of AMB. The complex was the most effective formulation against the DD8 strain of Leishmania donovani. It was unable to reverse the resistance of an AMBresistant L. donovani strain. In vivo LC-AMB was less efficient than AmBisome against L. donovani.There is a need for a new treatment for patients with visceral leishmaniasis (VL), particularly those with AIDS, since there is a high incidence of relapse after treatment with pentavalent antimonial drugs (11,19,25,32). Despite the recent success with miltefosine as an antileishmanial drug (17, 36), its use is limited because of the risk of the rapid development of resistance if it is used alone (7). The antifungal drug amphotericin B (AMB), a polyene antibiotic, is commonly used to treat leishmaniasis, but its application is limited because of its acute toxicity, which leads to a low therapeutic index when it is used as the traditional formulation, Fungizone (i.e., micelles mixed with the detergent deoxycholate) (18). In order to reduce this dose-limiting toxicity, different commercial lipid-based formulations have been developed and used in the clinical management of VL: AmBisome (4, 10), Abelcet (38, 39), and Amphotec (12). These have also been used as alternative treatments for mucocutaneous leishmaniasis (35,46). In some developed countries, AmBisome is now indicated as the first-line therapy against VL. However, the high prices of these formulations restrict their use in the regions most affected by these tropical diseases (24,15).Recently, several less expensive AMB formulations have been tested. Such formulations include the AMB derivatives prepared and described by Al-Abdely et al. (1) and Golenser et al. (14), which are water soluble and also less toxic. Heat treatment of Fungizone is an inexpensive technique for reduction of its toxicity (31), as is extemporaneous mixing of Fungizone with Intralipid (20, 40). Another particulate formulation with anionic lipids is stable and has good in vitro and in vivo efficacies (26). However, AmBisome remains the most effective formulation for the treatment of VL (46), and none of these formulations has yet been proved to be more active than the commercial ones.The present study was designed to evaluate the antileishmanial activity of a new lipid formulation of AMB in comparison with those of other commercially available lipid-AMB formula...

Production and Characterization of Stable Amphotericin-Resistant Amastigotes and Promastigotes of Leishmania mexicana

“…The use of AMB is now becoming widespread in Bihar (India) and Nepal (35), and previous reservations about the use of this potentially toxic drug have been alleviated (38). Experimental studies have also shown the possibility of reducing toxicity by heat treating AMB (4,28), and several groups are developing new formulations of AMB (1,12,13,23,24,33). Thus, it has recently been suggested that AMB should replace antimonials as the drug of choice in Bihar (37).…”

Central Nervous System Toxicity Associated with Liposomal Amphotericin B Therapy for Cutaneous Leishmaniasis

“…Review of the literature describing use of liposomal amphotericin B for the treatment of visceral or cutaneous leishmaniasis did not reveal any cases of confusion or any neurotoxicity related to treatment. 14,18,19 Although we cannot definitively prove that our patient's neurologic symptoms were caused by his liposomal amphotericin B treatment, we have no evidence for another more likely etiology by history, exam, and screening laboratories for metabolic causes. The time course over which he experienced this issue is consistent with the description in febrile neutropenic patients above as well as animal data detailing tissue half-lives of the drug.…”

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

“…Over recent years, lipid complex formulations of AmpB have been proposed, 57 showing interesting in vitro activity but less efficient than AmBisome in in vivo evaluations. More recently, liposomal formulations in which cholesterol was replaced by ergosterol, which constitutes 50% molarity of total lipids (Kalsome™ 10; Lifecare Innovations Ltd., Gurugram, India), have been evaluated.…”